Maintenance of homeostasis is of crucial importance to the survival of all living organisms. Any organism maintains its structure and functions by means of a multiplicity of dynamic equilibriums rigorously controlled by interdependent regulation mechanisms, in particular positive and negative feedback loops. Such mechanisms are set to react to every change in the environment, or to every random disturbance, through a series of modifications of equal size and opposite direction to those that created the disturbance. The goal of these modifications is to maintain the internal balances. Virtually all physiological processes or systems in mammals, such as humans, are subject to homeostatic monitoring and control. Examples include for instance temperature homeostasis, circadian homeostasis, metabolic homeostasis, endocrine homeostasis, neural homeostasis, respiratory homeostasis, and fluid homeostasis.
On the one hand, many diseases result from disturbance of homeostasis, a condition known as homeostatic imbalance. On the other hand, many diseases in fact cause homeostatic imbalance. Upon aging, every organism will eventually lose efficiency in one or more of its control systems. The inefficiencies gradually result in an unstable internal environment that increases the risk for illness. In addition, homeostatic imbalance is also responsible for the physical changes associated with aging. Even more serious than illness and other characteristics of aging is death. Diseases that result from a homeostatic imbalance, where nominal negative feedback mechanisms become overwhelmed and destructive positive feedback mechanisms then take over, include for example heart failure, diabetes, dehydration, hypoglycemia, hyperglycemia, gout, and any disease caused by a toxin present in the bloodstream. Diseases or disorders which can cause homeostatic imbalance, in particular imbalanced fluid or water homeostasis, include for example hyponatremia, hypernatremia, glucocorticoid deficiency, hypothyroidism, cirrhosis, congestive heart failure and advanced renal failure.
In many diseases and conditions, a favourable outcome of prophylactic and/or therapeutic treatments is strongly correlated with early and/or accurate prediction, diagnosis and/or prognosis and careful monitoring of the disease or condition. Therefore, there exists a continuous need for additional and preferably improved manners for early and/or accurate prediction, diagnosis and/or prognosis and monitoring of diseases and conditions to guide the treatment choices.
It may be clear that accurate and reliable diagnosis, prediction, prognosis and/or monitoring of homeostatic imbalance, and in particular imbalance of fluid or water homeostasis, as well as adequate differentiation between over-filled and under-filled conditions is needed for effective treatment. The present invention addresses the above needs in the art by identifying biomarkers for impaired fluid homeostasis and parameters associated therewith, and providing uses therefore.
Heart failure is a major public health issue in developed countries and is the cause of considerable morbidity and mortality among older adults. Overall, the changes in cardiac function associated with heart failure result in a decrease in cardiac output. It is usually a chronic disease characterised by frequent recurrent decompensation leading to worsening breathing problems. Moreover, 5 years after diagnosis 50% of heart failure patients will have died from the disease.
Several causes underlie heart failure. Specifically systolic dysfunction and diastolic dysfunction lead to cardiac remodelling and altered cardiac function, resulting in a decreased cardiac output. Both dysfunctions are characterized by defects in the pumping function of the heart. Systolic dysfunction results from a loss of intrinsic inotropy (contractility), most likely due to alterations in signal transduction mechanisms responsible for regulating inotropy, and is characterized by defects in emptying the heart, in particular the ventricle, of blood during contraction (i.e. the systole). Diastolic dysfunction occurs when the ventricle becomes less compliant (i.e., “stiffer”), which impairs ventricular filling and as such is characterized by defects in filling the heart, in particular the ventricle, with blood during relaxation (i.e. the diastole).
As such, the pathophysiology of systolic and diastolic dysfunction differs, as intrinsic compensatory mechanisms to cope with both dysfunctions differ. Although systolic and diastolic dysfunction share some common symptoms, the nature of treatment at least partially differs. Whereas both beta blockers and ACE inhibitors are indicated for the treatment of both systolic and diastolic dysfunction, possibly in combination with diuretics, inotropic drugs for instance, such as digoxin, are specifically indicated for the treatment of systolic dysfunction (and contra-indicated for the treatment of diastolic dysfunction) and for instance calcium channel blockers are specifically indicated for the treatment of diastolic dysfunction (and contra-indicated for the treatment of systolic dysfunction).
It may be clear that accurate and reliable diagnosis, prediction, prognosis and/or monitoring of systolic and/or diastolic dysfunction as well as the differentiation between both dysfunctions, is needed for adequate treatment. The present invention addresses the above needs in the art by identifying biomarkers for systolic dysfunction and parameters associated therewith, and providing uses therefore.